uPA/uPAR downregulation inhibits radiation-induced migration, invasion and angiogenesis in IOMM-Lee meningioma cells and decreases tumor growth in vivo.
Meningioma is a well-known tumor of the central nervous system, and is treated by surgical resection and/or radiation. Recently, ionizing radiation has been shown to enhance invasiveness of surviving tumor cells, and several proteolytic enzyme molecules, including urokinase plasminogen activator (uPA), seem to be upregulated after radiation. uPA and its receptor (uPAR) have been strongly implicated in tumor invasion, angiogenesis and progression. Hence, the tumor-associated uPA-uPAR system is considered a potential target for cancer therapy. In the present study, we show that radiation increases uPA levels in the IOMM-Lee meningioma cells, and subsequently, increases tumor invasion, migration and angiogenesis in vitro. Studies with signaling molecule inhibitors AG1478, U0126 and SB203580 (specific inhibitors of EGFR, MEK1/2 and p38 respectively) showed inhibition of uPA levels in both basal and irradiated-IOMM-Lee cells. The PI3K inhibitor (LY294002) and the AKT inhibitor (AKT inhibitor IV) also partially decreased uPA expression, whereas SP600125, a JNK inhibitor, did not affect uPA levels in either radiated or non-radiated cells. Further, a bicistronic plasmid construct with small interfering RNA (siRNA) against uPA and its receptor inhibited tumor invasion, migration and angiogenesis in radiation-treated IOMM-Lee cells. In addition, siRNA against uPA and its receptor inhibited subcutaneous tumor growth in athymic nude mice in combination with radiation in a synergistic manner. Thus, the specific targeting of proteases via RNA interference could augment the therapeutic effect of radiation and prevent the adverse effects resulting from tumor cells that receive sublethal doses of radiation within the tumor mass.
Kargiotis
Odysseas
O
Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine at Peoria, Peoria, IL 61605, USA.
Chetty
Chandramu
C
Gogineni
Venkateswara
V
Gondi
Christopher S
CS
Pulukuri
Sai Muralikrishna
SM
Kyritsis
Athanassios P
AP
Gujrati
Meena
M
Klopfenstein
Jeffrey D
JD
Dinh
Dzung H
DH
Rao
Jasti S
JS
D000818:Animals; D002196:Capillaries / Q000201:enzymology / Q000528:radiation effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000528:radiation effects*; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects*; D015536:Down-Regulation; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D008577:Meningeal Neoplasms / Q000201:enzymology / Q000473:pathology / Q000532:radiotherapy / Q000628:therapy*; D008579:Meningioma / Q000201:enzymology / Q000473:pathology / Q000532:radiotherapy / Q000628:therapy*; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009389:Neovascularization, Pathologic / Q000201:enzymology / Q000517:prevention & control*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D011878:Radiotherapy / Q000009:adverse effects; D055293:Receptors, Urokinase Plasminogen Activator / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering; D055293:Receptors, Urokinase Plasminogen Activator; C512478:EGFR protein, human; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D014568:Urokinase-Type Plasminogen Activator